1,1 - bis(3,4 - methylenedioxyphenyl)-2-methyl-3-(tert-amino)propanols and derivatives thereof



CROSS REFERENCE Eliiiitiliihti United States Patent 3,422,120 1,1BIS(3,4 METHYLENEDIOXYPI-IENYD-Z- METHYL-3-(TERT-AMINO)PROPANOLS ANDDERIVATIVES THEREOF Robert Bruce Motfett, Kalamazoo, Mich., assignor toThe 3,422,120 Patented Jan. 14, 1969 acids. The neutralization can becarried out by a variety of procedures known to the art to be generallyuseful for the preparation of amine acid addition salts. The choice ofthe most suitable procedure will depend on a variety of factors,including convenience of operation, economic glli c l' yt Kalamlloo, acorporation 0f 5 considerations, and particularly the solubilitycharactere aware istics of the particular free base, the acid, and theacid g gz i fa g May 1966 g g g addition salt. If the acid is soluble inwater, the free base 3 can be dissolved in water containing anequivalent amount 10 of the acid, and thereafter, the water can beremoved by This invention relates to new and useful chemical comevapo ain 9 the salt precipitates fmm pounds and more particularly, tol,l-bis(3,4-methylenef f Solution, P tlcular1y f q 6001M],pdioxyphenyl)-2-rnethyl-3-(tert-amino)propanol and the oration is notnecessary. If the acid is soluble in a relaacid addition salts thereoftively non-polar solvent, for example, diethyl ether or The1,l-bis(3,4-methylenedioxyphenyl)-2 methyl-B- diisopropyl ether,separate solutions of the acid and free (tert-amino)propanols of thepresent invention are reprebase In such a ent can be mixed in equivalentsented by the f l amounts, whereupon the acid addition salt will usuallyCH precipitate because of its relatively low solubility in the lnon-polar solvent. Alternatively, the free base can be OH R mixed withan equivalent amount of the acid in the presf sol nt f m derat larit forexam 1e a enceoa ve o o epo y, p,

lower alkanol, a lower alkanone, or a lower-alkyl ester of a loweralkanoic acid. Examples of these solvents are l ethanol, acetone, andethyl acetate, respectively. Subsecg d Formuiu quent admixture of theresulting solution of acid addition salt with a solvent of relativelylow polarity, for example, Where! R and 1 taken Separately are alkylhaving 'Q diethyl ether or hexane, will usually cause precipitation of 1to 4 carbon atoms, inclusive, and taken together Wlth the acid additionsalt. These acid addition salts are useful -N constitute a saturatedheterocyclic amino radical f upgrading the f bases sqkcted from P groupconsistiug 0f Pyrrolidino, P P The compounds of the Formula I, includingthe free dlflo, mOTPhOhIIP, N'methylplperalmobases and acid additionsalts, have anti-inflammatory ac- In the preceding Formula a p of alkylhavms tivity. For example, l,1-bis(3,4-methylenedioxyphenyl)- f 1 10 4Carbon a m lncluslve, are methyl, ethyl,2-methyl-3-diethylamino-propanol when administered or- P py butyl, and1501mm forms lhereofally at a dose of 45 mg. per kg. gives 37%inhibition of in- Compounds of Formula be PY P by react flarnmation asshown by the hind paw edema test in rats. g A- y yp f y wlth an alkylAdditionally, the compounds of the Formula I have y r -a )-p p(preferably a methyl or diuretic and CNS stimulating activity.1,l-bis(3,4-methylethyl ester) In an anhydrous solvent system, e.g.,diethyl enedioxyphenyl) 2 methy1 3 diethylaminopmpanol ether dlisopropylether, dlbu'ty1 ether tetrahydrofuran duces mild to excellent diureticresponse in rats at oral and the like; decomposing the reaction mixturein a con- 40 dosages f 5 a d 20 mg per kg. respectively. yflltkfnalmanner Such as y P i the mixture f i The free bases of the Formula Iform salts with fiuosilfied 105 Water, -8 hydrobromlc 0T hydrochlorlcacld, licic acid which are useful as mothproofing agents accordandcollecting the acid addition salt. The free base can be i to U5, Patents1,915,334 and 2,075,359. They also 'f f by dispersing the d additionSalt in Water and form salts with thiocyanic acid which condense withformy g the Solutlon, -i Wlth Sodium hydroxide. aldehyde to formresinous materials useful as pickling free base can be purified byconventional procedures such inhibitors according to 5 patents 2 425 32042 0 as by recrystallization from a suitable solvent, e.g., 2- 155 P P LethanOl, aCCIPHC, methyl ethyl ketom, y The free bases of this inventionalso form salts with pencyclohexane, andfhe 11keicillins. These saltshave solubility characteristics which 3Ajmethylenedloxyphenynlthlum canbe P p as 5 cause them to be useful in the isolation and purification ofdescribed y f and slouffel', Chem- 903 penicillins, particularly benzylpenicillin. Said salts can be and y Fem! and y, 'E- Chem 1363 formedeither by neutralization of the free base form of a compound of FormulaI, with the free acid form of a The alky1 y )P p penicillin, or by amethathetical exchange of the anion of Ployed in the foregoing Synthesiscan themselves be p an acid addition salt of a Formula I compound, forexam- Pared in accordance with known Procedures, for p ple the chlorideion of a hydrochloride, with the anionic by condensing a secondary amineof the formula: f f a i illi R The novel free bases of Formula I areuseful as acid acceptors in neutralizing undesirable acidity or inabsorbing an acid as it is formed in a chemical reaction, for

Bi example, a dehydrohalogenation reaction in which hywherein R and Rare as defined before, with an alkyl dmgen, i chlorme, bromme wdme areremoved (preferably methyl or ethyl) methacrylate. See Perrine, I. fromcmal E atoms- Org. Chem. 18, 898 (1953) and Vystrcil et al., Chem. Thefollowing examples illustrate the best mode con- Listy 44, 262 (1950).templated by the inventor for carry ng out the invention, Acid additionsalts of compounds of the Formula I but are not to be construed aslimiting the scope thereof. can be prepared by neutralization of thefree base with EXAMPLE I the appropriate amount of an inorganic ororganic acid, examples of which are hydrochloric, hydrobromic,sulfumethylenedloxyphenyl) z'melhy ammopropanol ric, nitric, prosphoric,acetic, lactic, benzoic, salicylic, glycolic, succinic, tartaric,maleic, malic, pamoic, cyclohexanesulfamic, citric and methanesulfonicacids, and like A solution of 162.8 g (0.81 mole) of3,4-methylenedioxybromobenzene in 500ml. of absolute ether was cooled to---50C. and 500 ml. (0.8 mole) of 15% butyllithum in hexane was addedduring 20 min. at 40 to 50 C. After stirring at 50 C. for 20 min., asolution of 34.6 g. (0.2 mole) of methyl2-methyl-3-diethylaminopropionate in 100 ml. of absolute ether wasslowly added. The mixture was stirred at 50 C. for 20 min., allowed toslowly warm to room temperature, and then refluxed for 3 hours. Afterstanding overnight, it was poured into ice water containing 1 mole ofhydrogen bromide, giving a dark gum which dissolved on adding more waterand ether. The aqueous layer was washed with ether and basified withsodium hydroxide, giving a dark oil; the mixture was extracted withether. The ether extract was washed with water and saturated sodiumchloride solution and dried over sodium sulfate. Filtration and removalof the ether gave 79 g. of dark syrup which partly crystallized on longstanding. The mixture was recrystallized from 450 ml. of 2-propanol(with decolorizing charcoal treatment), giving 51.2 g. (66.5%) ofcrystalline 1,1-bis (3,4-methylenedioxyphenyl)-2 methyl3-diethylaminopropanol, M.P. 9799 C. Recrystallization frommethylcyclohexane did not raise the melting point.

AnaIysis.-Calcd for C I-1 140 C, 68.55; H, 7.06; N, 3.63. Found: C,67.85; H, 6.86; N, 3.76.

By reacting 1,1 bis(3,4-methylenedioxyphenyl) 2-methyl-3-diethyla-minopropanol with acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric, acetic, lactic, benzoic,salicylic, glycolic, succinic, tartaric, malic, pamoic,cyclohexanesulfamic citric, and methanesulfonic acids, the correspondingacid addition salts can be obtained.

EXAMPLE 11 Following the procedure of the preceding Example 1, butsubstuting an equivalent amount each of methyl 2-methyl-3-(isopropylmethylamino)propionate, methyl 2-methyl-3-diisobutylaminopropionate, methyl 2-methyl-3-diisobutylaminopropionate, methyl 2-methyl-3-dimethylaminopropionate,methyl Z-methyl-3-pyrrolidinopropionate, methylZ-methyl-3-piperdinopropionate, methyl 2- methyl-3-morpholinopropionate,and methyl Z-methyl- 3' (N-methyl-piperazino)propionate for the methyl2- methyl3diethylamino-propionate of the example, there can be obtained:

1,1 bis(3,4-methylenedioxyphenyl)-2-methyl-3-(isopropylmethylamino)propanol,

l,l-bis(3,4-methylenedioxyphenyU-2 methyl 3-dibutylaminopropanol,

1,1 bis(3,4 methylenedioxphenyl)-2-methyl-3-diisobutylaminopropanol,

1,1 bis(3,4 methylenedioxyphenyl) 2-methyl 3-dimethylaminopropanol,

1,1 bis(3,4 methylenedioxyphenyl)-2-methyl-3-pyrrolidinopropanol,

I,l-bis(3,4-methylenedioxyphenyl) Z-methyl 3-piperi dinopropanol,

1,1 bis(3,4-methylenedioxyphenyl)-2-methyl-3-morpholinopropanol, and

1,1-bis(3,4-methylenedioxyphenyl) Z-methyl 3-(N-methylpiperazino)propanol, respectively. What is claimed is: 1. Acompound of the formula (i) \OH R 3 a C Hrwherein R and R takenseparately are alkyl having from 1 to 4 carbon atoms, inclusive, andtaken together with -N constitute a saturated heterocyclic amino radicalselected from the group consisting of pyrrolidino, piperizino,morpholino and N-methyl-piperazino, and the acid addition salts thereof.

2. A compound of claim 1 wherein R and R are ethyl, and the compound is1,1-bis(3,4-methylenedioxyphenyl)-2-methyl-3-diethylaminopropanol.

References Cited UNITED STATES PATENTS 1,964,973 7/1934 Bockmiihl et al.260-3405 X 2,765,307 10/1956 Schmidle 260-3405 X FOREIGN PATENTS 963,3047/1964 Great Britain.

NICHOLAS S. RIZZO, Primary Examiner.

JAMES H. TURNIPSEED, Assistant Examiner.

U.S. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,422,120 January 14, 1969 Robert Bruce Moffett It is certified thaterror appears in the above identified patent and that said LettersPatent are hereby corrected as shown below:

Column 1, line 70, "prosphoric" should read phosphoric Column 3, line28, "tartaric, malic" should read tartaric, maleic, malic line 37,"methyl-3-diisobutyl" should read methyl-3-dibutyl Column 4, line 27,"Zinc" should read piperidino Signed and sealed this 7th day of April1970.

(SEAL) Attest:

Edward M. Fletcher, J r.

Attesting Officer Commissioner of Patents WILLIAM E. SCHUYLER, JR.

1. A COMPOUND OF THE FORMULA